The role of costimulation is being studied in T cell repertoire selection. Mice that are either over-expressing or deficient in costimulatory molecules B7-1 and B7-2 or the costimulatory receptor CD28 are being analyzed for expressed T cell repertoire. Additional studies are assessing the role of CD40 and CD40L in T cell repertoire selection, and have indicated that expression of CD40L is critical to negative selection mediated by endogenous mtv gene products. Two pathways of negative selection have been identified. One pathway is CD40L-dependent and acts at a relatively early stage in intra-thymic development. The second is CD40L-independent and occurs later in intra-thymic or post-thymic development. The mechanism of CD40L dependence is being investigated. Costimulatory effects are also being analyzed in the setting of tolerance to male-specific antigens in pregnant mice. The effects of polymorphic self antigens on selection are also being studies using transgenic TCR and the introduction of self antigens through trans-species crosses of Mus musculus and Mus spretus mice. It has been found that self antigens of spretus origin can mediate negative selection of T cells expressing transgenic TCR. The identification of these self antigens and the mechanism of thymic deletion and peripheral tolerance are under study in this model system.